title: Cell-intrinsic regulation of murine dendritic cell function and survival by prereceptor amplification of glucocorticoid.
abstract: Although the inhibitory effects of therapeutic glucocorticoids (GCs) on dendritic cells (DCs) are well established, the roles of endogenous GCs in DC homeostasis are less clear. A critical element regulating endogenous GC concentrations involves local conversion of inactive substrates to active 11-hydroxyglucocorticoids, a reduction reaction catalyzed within the endoplasmic reticulum by an enzyme complex containing 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH). In this study, we found that this GC amplification pathway operates both constitutively and maximally in steady state murine DC populations and is unaffected by additional inflammatory stimuli. Under physiologic conditions, 11βHSD1-H6PDH increases the sensitivity of plasmacytoid DCs (pDCs) to GC-induced apoptosis and restricts the survival of this population through a cell-intrinsic mechanism. Upon CpG activation, the effects of enzyme activity are overridden, with pDCs becoming resistant to GCs and fully competent to release type I interferon. CD8α(+) DCs are also highly proficient in amplifying GC levels, leading to impaired maturation following toll-like receptor-mediated signaling. Indeed, pharmacologic inhibition of 11βHSD1 synergized with CpG to enhance specific T-cell responses following vaccination targeted to CD8α(+) DCs. In conclusion, amplification of endogenous GCs is a critical cell-autonomous mechanism for regulating the survival and functions of DCs in vivo.
authors.affiliation: School of Immunity and Infection, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;
authors.forename: Annelise
authors.initials: A
authors.lastname: Soulier
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Blois
authors.forename: Shivajanani
authors.initials: S
authors.lastname: Sivakumaran
authors.forename: Farnaz
authors.initials: F
authors.lastname: Fallah-Arani
authors.forename: Stephen
authors.initials: S
authors.lastname: Henderson
authors.forename: Barry
authors.initials: B
authors.lastname: Flutter
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Clare
authors.initials: C
authors.lastname: Bennett
authors.forename: S John
authors.initials: SJ
authors.lastname: Curnow
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D016827:CD8 Antigens; C431698:CD8alpha antigen; D003521:Cyclopropanes; D007370:Interferon Type I; C508012:N2-cyclopropylamine-guanosine; D011965:Receptors, Glucocorticoid; D051193:Toll-Like Receptors; D006151:Guanosine; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003552:11-dehydrocorticosterone; D003345:Corticosterone